ATM, a protein mutated in the human genetic disorder ataxia telengiactasia (AT) is activated by ionizing radiation damage to DNA and coordinately regulates this response with cell cycle checkpoint activation. Mounting evidence suggests that ATM is also involved in several other signaling pathways in response to a variety of stimuli. The applicant proposes to investigate the role of ATM in DNA damage recognition and will focus on three specific areas: the interaction of ATM with the Bloom syndrome protein, BLM, the relationship between ATM and BRCA1 (breast cancer susceptibility protein) in DNA damage signaling, and how ATM interacts with the Mre11/Rad50/p95 complex in responding to DNA double-strand breaks (DSBs) an activating cell cycle checkpoints. The specific aims are to: 1) explore further the relationship between ATM and BLM in DNA processing; 2) investigate the role of ATM in DNA damage induced signaling through BRCA1; and 3) study the phenotypic overlap between AT and Nijmegen Breakage Syndrome (NBS) with respect to DNA damage recognition. The ultimate goal is to define the role of ATM in response to radiation and delineate its involvement in cancer, which in the longer term will allow for the development of strategies designed to improve the therapeutic benefit of radiotherapy and provide a means of intervening in the development of this disease.